Abstract
Objective:
There is a paucity of data around the impact of exogenous hormones on future breast cancer risk in the setting of Lobular Neoplasia (LN). We sought to determine if patients with history of exogenous hormone use who develop LN are more likely to develop a future breast cancer.
Methods:
Following IRB approval, a single-institution retrospective review was conducted of patients diagnosed with LCIS or ALH between 1/2009 and 12/2017. Use of exogenous hormones and future breast cancer was examined. Data were analyzed using IBM SPSS version 29.0.2.0.
Results:
A total of 88 patients with LN were identified; 57 (65%) with LCIS and 31 (35%) with ALH. At time of LN diagnosis, 53 (60%) underwent surgical excision, 48 (39%) were followed in a high-risk clinic, and 13 (15%) took anti-estrogen therapy for risk reduction. 15 patients had a history of hormone therapy (HT) use prior to LN diagnosis (17%) and 3 (3%) started HT following LN diagnosis. Median overall follow-up was 9.7 years (interquartile range [IQR] 7.2–11.4). Eleven (13%) patients developed breast cancer. Comparing those who developed breast cancer vs. not, there was no difference in HT use (9% vs 21%, p=0.325), vaginal estrogen use (27% vs 9%, p=0.110), OCP use (54% vs 64%, p=0.675), or other hormone-based birth control (27% vs 14%, p=0.402).
Conclusion:
In a single-institution cohort with long-term follow up, future development of breast cancer in patients diagnosed with LN was not associated with prior use of HT, OCPs, vaginal estrogen or other hormone-based birth control use.
Keywords: Lobular Neoplasia, Breast Cancer, Lobular Carcinoma in Situ, Atypical Lobular Hyperplasia, Exogenous Hormones, Hormone Therapy
Graphical Abstract
Introduction
Exposure to exogenous hormones and future breast cancer risk has been studied for many years with associations described between elevated breast cancer incidence and use of estrogen plus progestin1–5. The impact of exogenous estrogens, either as birth control including oral contraceptive pills (OCPs) or as hormone therapy (HT) for the treatment of symptoms of menopause, and future breast cancer risk in women who are already considered high risk for other reasons is less well examined. This in turn makes clinical decision making regarding the use of exogenous hormones in women who are already considered high risk for breast cancer complicated to navigate and no clear guidelines exist.
Lobular neoplasia (LN) collectively refers to the proliferative, but non-invasive breast lesions atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS)6. LN is associated with an elevated lifetime risk of a future breast cancer, with between 18–21% of women developing breast cancer following LN diagnosis6–8. LCIS, although initially categorized as a non-obligate precursor for breast cancer, is now recognized as a marker for an increased likelihood of developing an invasive carcinoma in either breast, independent of the LCIS lesion itself2. Previous literature has suggested that that age and menopausal status do not contribute to the likelihood of developing LN8, yet a recent study utilizing the National Institutes of Health-AARP Diet and Health Study Cohort found that women who were exposed to menopausal hormone therapy were more likely to develop LCIS even with less than 5 years of exposure9.
Once an individual is diagnosed with LN there is a paucity of data around the impact of HT and other exogenous hormones, including oral contraceptive pills (OCPs) on the risk of developing a future breast cancer. It is unknown if prior exogenous hormone exposure is associated with an even higher risk of developing a future breast cancer, beyond that conferred by the presence of LN alone. Risk management for patients with LN includes supplemental screening, such as a breast MRI, and discussion of anti-endocrine therapy for risk reduction10. Understanding if prior use of exogenous hormones, such as HT or OCPs, is associated with an even higher risk for a future breast cancer may lead to an opportunity to escalate risk mitigation strategies. We hypothesize that prior use of exogenous hormones, specifically HT, may be associated with increased future breast cancer risk in those diagnosed with LN. Therefore, the objective of this study is to determine the incidence of a future breast cancer in patients with LN and a history of exogenous estrogen use versus those with LN but without prior exposure to exogenous hormones.
Methods
Following Institutional Review Board (IRB) approval, a retrospective cohort study was conducted of consecutive patients ≥18 years old with LCIS or ALH diagnosed by image-guided biopsy between January 2009 and December 2017. The time period of the study was chosen to ensure ≥8 years of potential follow-up and identification of future breast cancers. Patients were identified through a pathology database of patients at a single academic institution. All subtypes of LCIS were included. Given a low number of non-classic subtypes within the cohort, subgroups by non-classic subtype could not be analyzed separately. Patients with a prior history of breast cancer, concurrent breast cancer (either ipsilateral or contralateral), known genetic mutation, or concurrent atypical ductal hyperplasia (ADH) were excluded. If patients underwent surgical excision of the LN lesion (also referred to as excisional biopsy) following diagnosis of LN, that surgical pathology was reviewed; patients upgraded to either ductal carcinoma in situ or invasive carcinoma at the time of excisional biopsy were excluded. Medical record data were abstracted and securely stored using REDCap hosted at the University of Wisconsin-Madison.
Variables collected included demographic information, HT use and duration, breast cancer risk factors including gynecologic history, family history, genetic mutation status, history of prior mammographs, breast density and histopathology. Menopausal status at time of LN diagnosis was determined by patient report and documentation within the electronic medical record of last menstrual period. Variables regarding management of LN and estrogen exposure were also collected including surgical excision of the initial LN lesion, referral to high-risk clinic following LN diagnosis, recommendation for risk-reducing medication, endocrine therapy use following LN diagnosis and duration, use of HT following LN diagnosis, use of other exogenous estrogens including vaginal estrogens, OCPs, and other hormone-based birth control use. Exogenous estrogen type, use and duration was determined based on patient report as it was documented in provider clinical notes. Duration of OCP and HT use prior to diagnosis of LN was recorded if documented in the medical chart by a provider seeing the patient for discussion of LN management. Primary outcome was incidence of future breast cancer. Future breast cancer was defined as either invasive carcinoma or ductal carcinoma in situ in either breast.
Data were analyzed using IBM SPSS version 29.0.2.0. Variables were analyzed using Fisher’s Exact Test and Mann-Whitney U test as appropriate. Significance was set as p-value <0.05.
Results
A total of 88 patients with LN were identified; 57 (65%) with LCIS and 31 (35%) with ALH. All patients were biologic females and median age at the time of diagnosis was 52.75 (interquartile range [IQR] 48.56–58.78). At time of LN diagnosis, 29 patients (33%) were pre-menopausal, 49 (55.7%) were post-menopausal, and 6 (6.8%) were considered peri-menopausal by their medical provider. Menopausal status at LN diagnosis was unknown in 4 (4.5%) of patients. The screening mammogram identifying the LN was the baseline mammogram in 9 (10%) patients and 46 (52%) had a screening mammogram within the last 2 years, prior to LN diagnosis. Four (4.5%) patients had a prior history of a high-risk lesion (LN n=3, ADH n=1) diagnosed before the study period. Additional patient characteristics and breast cancer risk factors are described in Table 1. At the time of LN diagnosis, 53 (60%) underwent surgical excision and 48 (39%) were followed in a high-risk clinic (Table 2). Although 57 (64.8%) had a documented recommendation for anti-estrogen therapy for risk reduction following diagnosis of LN, only 13 (15%) were prescribed anti-estrogen medications.
Table 1.
Univariate analysis of future breast cancer and patient demographics in patients with lobular neoplasia (LN)
| All Patients with LN (n=88) | Diagnosed with LN and cancer (n=11) | LN but no future cancer diagnosis (n=77) | P-value | |
|---|---|---|---|---|
| Age at diagnosis (median, IQR) | 52.8 (48.6–58.8) | 50.0 (49.3–57.9) | 53.3 (48.0–59.3) | 0.689 |
| Female Sex | 88 (100%) | 11 (100%) | 77 (100%) | >0.99 |
| Race | 0.780 | |||
| White | 81 (92%) | 11 (100%) | 70 (91%) | |
| Black | 2 (2%) | 0 (0%) | 2 (3%) | |
| Asian | 2 (2%) | 0 (0%) | 2 (3%) | |
| Other/Unknown | 3 (3%) | 0 (0%) | 3 (4%) | |
| Ethnicity | 0.864 | |||
| Hispanic | 1 (1%) | 0 (0%) | 1 (1%) | |
| Non-Hispanic | 86 (97%) | 11 (100%) | 75 (97%) | |
| Unknown | 1 (1%) | 0 (0%) | 1 (1%) | |
| Prior high-risk lesion | 4 (4.5%) | 1 (9%) | 3 (4%) | 0.518 |
| LCIS * | 3 (3%) | 1 (9%) | 2 (3%) | |
| ALH * | 1 (1%) | 1 (9%) | 0 (0%) | |
| ADH * | 1 (1%) | 0 (0%) | 1 (1%) | |
| LCIS | 57 (65%) | 9 (82%) | 48 (62%) | 0.206 |
| ALH | 31 (35%) | 2 (18%) | 29 (38%) | 0.206 |
| LCIS subtype | 0.630 | |||
| Classic | 37 (42%) | 5 (45%) | 32 (42%) | |
| Pleomorphic/Florid/Apoc rine | 2 (2.3%) | 0 (0%) | 2 (3%) | |
| Unspecified | 19 (22%) | 4 (36%) | 15 (19%) | |
| Other concurrent high-risk lesion (except ADH – pts excluded) | 5 (6%) | 0 (0%) | 5 (6.5%) | 0.192 |
| History of prior breast biopsy | 26 (29.5%) | 7 (64%) | 19 (25%) | 0.029 |
| Breast density on MMG | 0.271 | |||
| Entirely fatty | 0 (0%) | 0 (0%) | 0 (0%) | |
| Scattered | 23 (26%) | 1 (9%) | 22 (29%) | |
| Heterogeneously dense | 56 (64%) | 9 (82%) | 47 (84%) | |
| Extremely dense | 3 (3%) | 1 (9%) | 2 (3%) | |
| Unknown | 5 (6%) | 0 (0%) | 5 (6.5%) | |
| BMI (median, IQR) | 27.4 (23.7–31.0) | 30.5 (25.0–36.6) | 27.0 (23.5–30.4) | 0.178 |
| Prior hysterectomy | 14 (16%) | 0 (0%) | 14 (18%) | 0.123 |
| Number of gestations (median, IQR) | 2 (1.0–3.0) | 2 (1.0–2.0) | 2 (1.0–3.0) | 0.459 |
| Number parity/live births (median, IQR) | 2 (0.0–2.0) | 2 (0.0–2.0) | 2 (0.0–2.0) | 0.242 |
| Age at onset of menses (median, IQR) | 13 (12.0–13.25) | 13 (12.0–13.25) | 13 (12.0–13.5) | 0.997 |
| Fertility status at time of LN diagnosis | 0.026 | |||
| Pre-menopausal | 29 (33%) | 8 (73%) | 21 (27%) | |
| Peri-menopausal | 6 (7%) | 0 (0%) | 6 (8%) | |
| Post-menopausal | 49 (56%) | 3 (27%) | 46 (60%) | |
| Unknown | 4 (4.5%) | 0 (0%) | 4 (5%) | |
| Any family history Breast Cancer | 57 (65%) | 7 (67%) | 50 (65%) | 0.933 |
| Strength of family history of breast cancer | 0.521 | |||
| 1st degree | 27 (31%) | 3 (27%) | 24 (31%) | |
| 2nd degree | 24 (27%) | 4 (36%) | 20 (26%) | |
| Other/Unknown degree | 6 (7%) | 0 (0%) | 6 (78%) | |
| Age of Family Member with breast cancer history | 0.619 | |||
| <50 at diagnosis | 23 (26%) | 4 (36%) | 19 (25% | |
| >50 at diagnosis | 21 (24%) | 2 (18%) | 19 (25%) | |
| Unknown age at diagnosis | 13 (15%) | 1 (9%) | 12 (16%) | |
| Any family history Ovarian Cancer | 18 (20%) | 3 (27%) | 15 (19%) | 0.549 |
One patient had multiple types of high-risk lesions identified on follow-up, totals therefore exceed 100%. LN=Lobular neoplasia, IQR=interquartile range, LCIS=lobular carcinoma in situ, ALH=atypical lobular hyperplasia, ADH=atypical ductal hyperplasia
Table 2.
Management of patients following initial diagnosis of lobular neoplasia (LN)
| All Patients (n=88) | Diagnosed with cancer (n=11) | No cancer diagnosis (n=77) | P-value | |
|---|---|---|---|---|
| Recommended anti-endocrine therapy after LN diagnosis | 57 (65%) | 10 (91%) | 47 (61%) | 0.152 |
| Took anti-endocrine therapy after LN diagnosis | 13 (15%) | 0 (0%) | 13 (17%) | 0.119 |
| Underwent excisional biopsy or other surgical excision of LN lesion | 53 (60%) | 8 (73%) | 45 (58%) | 0.618 |
| Years between LN diagnosis and cancer diagnosis (median, IQR) | 5.4 (2.7 – 6.8) | 5.4 (2.7 – 6.8) | - | - |
| Future LN or other high-risk lesion identified | 9 (10%) | 3 (27%) | 6 (8%) | 0.046 |
| LCIS * | 6 (7%) | 3 (37%) | 3 (4%) | |
| ALH * | 3 (3%) | 1 (9%) | 2 (3%) | |
| ADH * | 2 (2%) | 1 (9%) | 1 (1%) | |
| Unknown * | 1 (1%) | 0 (0%) | 1 (1%) |
Three patients had multiple types of high-risk lesions identified on follow-up, totals therefore exceed 100%. LN=Lobular neoplasia, IQR=interquartile range, LCIS=lobular carcinoma in situ, ALH=atypical lobular hyperplasia, ADH=atypical ductal hyperplasia
Exposure to exogenous estrogens prior to LN diagnosis was examined as the primary exposure of interest. Overall, 15 patients had a documented history of HT use prior to LN diagnosis (17%), with only 2 (2%) actively taking HT at time of LN diagnosis; 3 (3%) started HT following LN diagnosis. An additional 10 (11%) had a history of vaginal estrogen use, 55 (63%) OCP use, and 14 (16%) other hormone-based birth control use including but not limited to depo-medroxyprogesterone acetate, hormonal IUDs, and the vaginal contraceptive ring.
Median overall follow-up was 9.7 years (interquartile range [IQR] 7.2–11.4). Eleven (13%) patients developed breast cancer a median of 5.4 years ([IQR] 2.7–6.8) after LN diagnosis (Table 1). Two developed a future cancer in the same location as their LN 6 and 8 years after LN diagnosis. All other subsequent breast cancers occurred in either the contralateral breast or a different quadrant of the ipsilateral breast. Comparing those who developed breast cancer versus those who did not, there was no difference in HT use (n=1 [9%] vs n=16 [21%], p=0.325), vaginal estrogen use (n=3 [27%] vs n=7 [9%], p=0.079), OCP use (n=6 [54%] vs n=49 [64%], p=0.675), or other hormone-based birth control (n=3 [27%] vs n=11 [14%], p=0.402) (Table 3). Zero patients who developed breast cancer took anti-endocrine therapy for risk reduction following LN diagnosis (n=0 [0%] vs. n=13 [16.8%] of those who did not develop a future cancer, p=0.119). Median duration of HT use prior to LN diagnosis for patients who did not develop breast cancer was 110.5 months ([IQR] 42–138), and the one patient that developed future breast cancer utilized HTs for 108 months prior to LN diagnosis. Statistical significance for HT duration could not be calculated due to low event numbers. Duration of OCP use was not higher as expected in the future breast cancer cohort, but rather those who developed breast cancer had a statistically shorter reported duration of lifetime OCP use with median of 24 months ([IQR] 3–96) of use versus 120 months ([IQR] 60–180) in those patients who did not develop cancer, p=0.017.
Table 3.
Univariate analysis of exogenous hormone use and incidence of future breast cancer
| All Patients (n=88) | Diagnosed with cancer (n=11) | No cancer diagnosis (n=77) | P-value | |
|---|---|---|---|---|
| Any HT use | 17 (19%) | 1 (9%) | 16 (21%) | 0.358 |
| History of HT prior to LN diagnosis | 15 (17%) | 1 (9%) | 14 (18%) | 0.453 |
| Actively taking HT at time of LN diagnosis | 2 (2%) | 0 (0%) | 2 (3%) | 0.589 |
| Started HT after LN diagnosis | 3 (4%) | 0 (0%) | 3 (4%) | 0.505 |
| Months reported of HT use (median, IQR) | 108 (48 – 132) | 108 (108–108) | 111 (42–138) | N/A |
| Vaginal estrogen use | 10 (11%) | 3 (27%) | 7 (9%) | 0.079 |
| OCP use | 55 (62.5%) | 6 (55%) | 49 (64%) | 0.675 |
| Months reported of OCP use | 96 (36–168) | 24 (3–96) | 120 (60–180) | 0.017 |
| Other hormone-based birth control use | 14 (16%) | 3 (27%) | 11 (14%) | 0.402 |
HT=Hormone therapy, LN=Lobular neoplasia, IQR=interquartile range, OCP=oral contraceptive pill
Other clinical variables significantly associated with future breast cancer diagnosis on univariate analysis included fertility status at time of LN diagnosis, with patients who developed a future cancer being more likely to be pre-menopausal at time of LN diagnosis (n=8/11 [72.7%] vs n=21/77 [27.3%] pre-menopausal at time of diagnosis who did not develop cancer, p=0.026), history of a prior breast biopsy (n=7/11 [64%] vs n=19/77 [25%], p=0.029), and having an additional LN or other high-risk lesion identified on subsequent screening imaging after the initial diagnosis of LN (n=3/11 [27%] vs. n=6/77 [8%] p=0.46) (Table 1).
Discussion
In a small single-institution cohort with long-term follow up, identification and development of breast cancer in patients diagnosed with LN was not associated with documented history of HT, OCPs, vaginal estrogen or other hormone-based birth control use. For years, the suspicion of increased breast cancer risk from use of exogenous estrogens has caused uncertainty among clinicians and patients. The findings of this single-institution cohort suggest that patients with newly diagnosed LN and prior exogenous hormone exposure may not have an increased risk of developing a future breast cancer beyond that confirmed by diagnosis of LN alone. Given the small size and limited power of our study however, external validation in a larger multi-institutional prospective study is needed prior to implementing these findings clinically. At present these data provide promising preliminary results that clinicians may need not alter their recommendations regarding risk management and risk-reducing medication for patients with LN based on prior exogenous hormone exposure.
Prior studies have examined the types of breast lesions including breast cancers that develop in women with prior HT. Mullooly et al. conducted a large cohort study utilizing the National Institutes of Health-AARP Diet and Health Study Cohort of 190,325 post-menopausal women and found that development of LCIS was associated with menopausal hormone therapy use, regardless of duration, with a stronger hazard ratio (HR) than either development of ductal carcinoma in situ (DCIS) or invasive disease. Short-term (<5 years) but current HT use was associated with development of LCIS with a HR of 2.59 (95% confidence interval [CI] 1.65–4.05), but HR 1.44 (95% CI 1.22–1.71) for DCIS and HR 1.22 (95% CI 1.13–1.32) for invasive ductal carcinoma9. Interestingly, Gapstur et al. analyzed a cohort of 37,105 post-menopausal women through the Iowa Women’s Health Study and found that those who had a history of HT use and developed breast cancer were more likely to have invasive disease with a favorable histology,5. Together, these data suggest that prior HT use in women and breast cancer risk is complex, potentially with variable but potentially less aggressive biology.
Use of oral contraceptives (OCPs) has previously been shown to not be associated with an increased risk of developing LCIS, although data is limited exploring impact of OCP use in the setting of LN11. Using data from the Collaborative Breast Cancer Study, Nichols et al. investigated the use of OCPs and risk of developing in situ breast carcinoma in a large case-control study in which they examined women with DCIS and LCIS11. In a sub cohort analysis including specifically 223 women with LCIS, they found that any prior or current OCP use was not associated with development of LCIS (OR 1.04, 95% CI 0.77–1.40). These data support the present study’s findings that prior OCP use likely does not alter the risk of developing a future breast cancer in women with LN, beyond what is already known to be conferred with a diagnosis of LN.
The use of vaginal estrogen has been safely demonstrated in women even following a diagnosis of breast cancer12. Large cohort studies examining breast cancer outcomes in women exposed to vaginal estrogen have demonstrated no difference in breast-cancer specific survival, likely due to very low levels of systemic absorption13–14. Although there is a paucity of data examining vaginal estrogen use in patients with LN, these findings for patients with invasive breast cancer are supportive that vaginal estrogen use in patients with LN is unlikely to impact future breast cancer risk.
Limitations of the present study exist. As mentioned previously, we acknowledge that our study is a single institution cohort with a small future breast cancer subcohort as well as a small number of patients who were actively taking HT or continued to take HT following LN diagnosis. Given this, associations may exist with important clinical features but our study was underpowered to detect those associations. Future multi-centered studies are necessary for validation of the present findings. Additionally, although we examined incidence, given the retrospective nature of the study, we were unable to determine duration of anti-estrogen therapy for risk reduction with enough granularity to consider accurate. Similarly, given the retrospective nature of the cohort, duration of exposure to exogenous hormones, including HT and OCPs, although reported here, is reliant upon documentation in the medical chart, which is subject to recall bias of the patient and provider. Because of the small sample size and limited data on the exact type of prior contraceptive and hormone therapy use, we are also unable to stratify these findings by formulation of exogenous hormone to which a patient was exposed. Future long term, prospective studies are necessary to validate our present findings.
Conclusion
In this small, single-institution, retrospective cohort review, prior exogenous hormone use, including HT, OCPs and vaginal estrogen in patients diagnosed with LN was not associated with any further risk of a future breast cancer, beyond that already conferred by the diagnosis of LN. Although additional validation with a larger cohort, with more granular data regarding the type of exogenous hormone exposure and duration is necessary, these data suggest that it is likely that patients with LN who have a prior history of exogenous hormone exposure may not have any additive risk of a future breast cancer beyond that conferred by the diagnosis of LN itself.
Acknowledgments/Funding
Research reported in this publication was supported in part by the Office of Research on Women’s Health, Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) program, the Office of The Director, National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases under award K12AR084227. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
This CSA Societal Paper was presented at the Central Surgical Association 83rd Annual Meeting on June 6th 2026 in Chicago, IL.
Disclosures: ACB received honoraria for an invited lecture from Intellisphere on a topic unrelated to the present work. LGW is a founder and minority stock-owner in Elucent Medical. No Artificial Intelligence (AI) was used in the development of this manuscript.
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